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研究生:盧珮珊
研究生(外文):Pei-ShanLu
論文名稱:探討Nucleolin在肺癌形成中的轉錄機制
論文名稱(外文):To dissect the transcriptional mechanism of nucleolin in lung cancer tumorigenesis
指導教授:洪建中洪建中引用關係
指導教授(外文):Jan-Jong Hung
學位類別:碩士
校院名稱:國立成功大學
系所名稱:生物資訊與訊息傳遞研究所
學門:生命科學學門
學類:生物訊息學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:中文
論文頁數:83
中文關鍵詞:NucleolinSp1EGFRKras肺癌
外文關鍵詞:NucleolinSp1EGFRKrasLung cancer
相關次數:
  • 被引用被引用:0
  • 點閱點閱:183
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  • 下載下載:13
  • 收藏至我的研究室書目清單書目收藏:0
肺癌為十大癌症之一,在世界衛生組織的統計之下,每年約有 140 萬人死於肺癌。而且合併計算其它併發症的病人,肺癌的五年存活率只有 15.2%,相較低於其他癌症。 Nucleolin在細胞具有許多的功能,包含了調控細胞增生、細胞凋亡、mRNA 的穩定性等。 先前的研究已經指出 nucleolin 會在腫瘤細胞中大量表現,然而其分子機轉仍然不清楚。在先前實驗室建立的Kras 誘導肺癌轉殖鼠看到隨著四環黴素(Doxycyclin) 的餵食會有腫瘤形成的現象。在這些肺癌腫瘤中我們去分析nucleolin mRNA的表現量,的確隨著四環黴素的餵食時間增加而增加。這樣的結果,讓我們懷疑在肺癌癌化過程中,Kras路徑對於nucleolin的累積是否扮演重要的腳色。非小細胞肺癌的病患中常常可以偵測到基因的突變,約三到五成為腺癌(adenocarcinoma)的類型,其中Kras突變好發於西方人,EGFR突變則好發於東方人。實驗室先前的研究也指出,隨著四環黴素的餵食Kras誘導肺癌轉殖鼠,specific protein 1 (Sp1) 同樣也會高度表現。在肺癌癌化過程中,Sp1高度表現和nucleoiln的累積是否有關連性目前仍然未知。首先,我們利用FTI-276 (Kras抑制劑) 去處理細胞,發現nucleolin的轉錄活性(transcriptional activity) 會被抑制。之後我們利用EGF去處理細胞發現會使nucleolin的蛋白質表現、mRNA 和轉錄活性都上升;反之處理Gefinitib (EGFR 抑制劑) 則會抑制nucleolin的轉錄活性。此結果顯示Kras 及EGFR調控路徑有可能在肺癌形成中對nucleolin的累積有重要的影響。為了深入了解nucleolin 在肺癌形成中的轉錄機制,我們分析了nucleolin的啟動子(promoter),發現有5個 Sp1結合位置在 nucleolin啟動子上。而這些Sp1 結合位置的刪除會明顯地降低 nucleolin的轉錄活性。此外,過度表現Sp1會增加nucleolin表現量; 反之抑制Sp1,nucleolin則會降低。最後,實驗室建立的EGFR (exon19 deletion) 誘導肺癌轉殖鼠在肺癌形成中,nucleolin會大量表現。綜合以上實驗我們得知Sp1可能會透過Kras及EGFR的路徑參與在nucleolin的上升中,這些結果可以讓我們更加了解肺癌形成的機制及nucleolin在其中扮演的角色,而且進一步有助肺癌的研究及治療。
Lung cancer is the most common cause of death in both men and women throughout the world. Survival rates for lung cancer are generally lower than those for most cancers, with an overall five-year survival rate for lung cancer of about 15.2% compared to other cancer for example 64.4% for colon cancer. Previous studies reveal that nucleolin is a multifunctional protein involved in RNA stability, apoptosis and so on. In the past cancer research, nucleolin was found to be accumulated in tumerigenesis. However, the transcriptional mechanism remains unclear. Our preliminary data found that nucleolin was also accumulated in Kras-induced lung cancer transgenic mice, implying that Kras-pathway might be related to nucleolin accumulation. In western countries, the Kras mutation rate is high in patients with NSCLC, especially in those with adenocarcinoma (30%-50%), but high EGFR mutation rates in East Asia. In addition, our previous study indicated that specific protein 1 (Sp1) level was highly increased and required for lung tumor growth in transgenic mice bearing Kras-induced lung tumors under the control of doxycycline. Whether the nucleoiln accumulation in lung tumorigenesis is associated with highly expressed Sp1 in lung cancer is still unknown. Here, inhibition of Kras activity by inhibitor, FTI-276, declined the transcriptional activity of nucleolin. In addition, we also used EGF or Epithelial Growth Factor Receptor (EGFR) inhibitor, Gefitinib, to treat cell, and found that nucleolin could be activated or repressed in its protein level, mRNA level and transcriptional activity, respectively. These results figure out EGFR- and Kras- pathways induced in lung cancer formation might be important for nucleolin accumulation. To further address the transcriptional mechanism of nucleolin in lung cancer formation, we analyze the promoter of nucleolin and found 5 Sp1 binding site on the promoter of nucleolin. Deletion of promoter sequence that contain Sp1 binding sites significantly decrease nucleolin transcriptional activity. Moreover, overexpression of Sp1 will induce nucleolin up-regulation. Finally, the protein level of nucleolin in EGFR (exon19 deletion)-driven lung cancer transgenic mice highly increased. These results will let us to understand the transcriptional mechanism of nucleolin in lung cancer tumorigenesis clearly and benefit to lung cancer study.
目錄
摘要 II
Abstract IV
誌謝 VI
縮寫檢索表 VII
目錄 IX
第一章 序論 1
1.前言 1
2.肺癌 1
2-1肺癌定義 1
2-2肺癌中的基因突變 2
2-3肺癌中 Kras、EGFR 基因突變 3
3.Nucleolin 5
3-1 Nucleolin之結構及功能簡介 5
3-2 Nucleolin 與腫瘤的關連性 6
3-3片段化的 nucleolin (c-nucleolin) 6
4.Sp1 6
5.研究目標 7
第二章 實驗材料 8
1.化學試劑 8
2.試劑組 10
3.抗生素 11
4.抗體 11
5.細胞培養相關物品 12
5-1細胞培養液 12
5-2 細胞培養相關材料 12
6.實驗用器材 13
7.其他實驗相關器材 13
第三章 實驗方法 14
1.細胞株的培養 14
1-1.細胞種類 14
1-2.培養方式 15
1-3.繼代培養(subculture) 15
2.條件式基因轉殖鼠(conditional transgenic mice) 15
2-1.條件式Kras基因轉殖鼠(Condition Kras activated transgenic mice)原理 15
2-2.條件式EGFR基因轉殖鼠(Condition EGFR activated transgenic mice)原理 16
2-3 .PCR基因定型 (PCR genotyping) 16
3.蛋白質分析(Protein level analysis) 18
3-1.全細胞液的抽取 (Total cell lysate extraction) 18
3-2肺組織液的抽取 (Total lung tissue extraction) 18
3-3硫酸十二酯鈉聚丙烯醯胺凝膠法(SDS-PAGE) 19
3-4.濕式蛋白質電泳轉漬法 (Transfer) 21
3-5阻斷 (Blocking) 21
3-6免疫染色 (Immunoblotting) 21
4.DNA level analysis 22
4-1. Cell RNA萃取 (RNA extraction) 22
4-2反轉錄聚合酶連鎖反應 (RT-PCR) 23
4-3.聚合酶連鎖反應 (PCR)條件 23
5.建構載體 (Nucleolin promoter construct) 24
5-1.設計引子 24
5-2.聚合酶連鎖反應 (PCR)條件 24
5-3.yT&A 載體選殖(yT&A cloning) 25
5-4.質體製備 (plasmid preparation) 25
5-5.選殖 cloning 26
6.報導基因測試 (Reporter gene assay) 27
6-1.大量抽取質體DNA (Plasmid) 27
6-2.暫時性轉染 (Transient transfection) 27
6-3.luciferase活性的測定 28
7.點突變質體製備(Site-directed mutagenesis) 29
8.免疫組織染色 (Immunohisochemistry,IHC) 31
8-1.原理 31
8-2.脫蠟 31
8-3.Antigen Retriever 31
8-4.染色 31
9.細胞靜默 Sp1系統(Sp1 knockdown) 32
10.過度表現Sp1系統 (Sp1 overexpression) 33
第四章 實驗結果 34
1.Nucleolin在肺癌形成中會大量累積 34
1-1.Nucleolin在肺癌細胞株中大量表現 34
1-2.Nucleolin在肺癌轉殖鼠中大量表現 34
2 Nucleolin的累積和肺癌預後相關性 36
2-1.Nucleolin在人類肺癌檢體中會大量表現 36
2-2.Nucleolin累積對肺癌病人的預後率呈現負相關 36
3.癌細胞中,EGFR 及Kras路徑會參與調控nucleolin的轉錄活性 36
3-1 Kras及EGFR 路徑的活化或抑制會影響Nucleolin的 mRNA 層次 37
3-2 Kras及EGFR 路徑的活化或抑制會影響Nucleolin的轉錄活性 38
4.癌細胞中, EGFR 及Kras路徑的調控會影響Nucleolin表現量 38
5.肺癌進程中,Sp1 會促進nucleolin 的轉錄活性上升 39
5-1 在A431、H1299細胞株過度表現Sp1會造成nucleolin表現量上升 39
5-2 在A431、H1299細胞株抑制Sp1會造成nucleolin表現量下降 40
5-3 A431經由EGF的處理對nucleolin 啟動子280-750區域的轉錄活性有極大助益 40
5-4 Sp1會透過EGFR及Kras路徑調控nucleolin 41
第五章 實驗討論 43
1.Nucleolin和癌症 43
2.Nucleolin累積的機制 44
3.造成Sp1累積的機轉 45
4.總結 46
第六章 參考文獻 47

實驗結果 55
Figure 1 56
Figure 2 57
Figure 3 58
Figure 4 59
Figure 5 60
Figure 6 61
Figure 7 62
Figure 8 63
Figure 9 64
Figure 10 65
Figure 11 66
Figure 12 67
Figure 13 68
Figure 14 69
Figure 15 70
Figure 16 71
Figure 17 72
Figure 18 73

附錄 74
Appendix.1 75
Appendix.2 76
Appendix.3 77
Appendix.4 78
Appendix.5 79
Appendix.6 80
Appendix.7 81
Appendix.8 82
Appendix.9 83




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